The morphinan compounds are a group of structurally related alkaloids that can act as opiate receptor agonists or opiate receptor antagonists. Opiate receptor agonists such as e.g. morphine, codeine, hydrocodone, oxycodone, hydromorphone, oxymorphone, and nalbuphine, are of use as analgesics for pain relief. Compounds such as nalmefene, naltrexone and naloxone are opiate receptor antagonists useful for the treatment of substance abuse or to reverse the effects of opiate agonists.

A process for preparing 14-hydroxymorphinone by O-demethylating 14-hydroxy-codeinone is described by Ulrich Weiss in Journal of Organic Chemistry, p. 1505-1508 (1957), by brief treatment of 14-hydroxycodeinone with a concentrated aqueous solution of hydrobromic acid at 120° C., removal of non-phenolic material by extraction with chloroform from alkaline medium, and extraction of the phenolic reaction products with chloroform or chloroform-ethanol at pH=8-9. The reported yields are modest and variable ranging between 35% and 52%. Also undesired hydration of the double bond in 14-hydroxymorphinone was also observed.

Hence there is a need for a more efficient process with a higher yield and little or no formation of the undesired 8,14-dihydroxydihydromorphinone.
Another process for process for preparing 14-hydroxymorphinone by O-demethylating 14-hydroxy-codeinone is described by Zhang A. et al. in Organic Letters, vol. 7, no. 15, 3239-3242 (2005) by treatment of 14-hydroxycodeinone with BBr3 in anhydrous dichloromethane. According to the Supporting Material of the Zhang paper 14-hydroxymorphinone was obtained as a pure white solid with a 70% yield. A feasibility study was done to confirm the yield of said described procedure and to check the quality of the obtained material. The procedure in the Zhang paper could not be reproduced successfully. It was found that full conversion to 14-hydroxymorphinone could not be found even after elongated stirring up to 4 days and chromatographic analysis showed large amounts of different byproducts. Following the reported quench procedure and subsequent extraction procedure in accordance with the Zhang paper, the yield was only 15-25% crude product with 70-85% purity that contained up to 10% unreacted 14-hydroxycodeinone. LC-MS analysis of the reaction mixture showed that during the aqueous work-up procedure HBr was formed when unreacted BBr3 was hydrolysed resulting in a side reaction of HBr addition to the double bond.

Better results were achieved by quenching the reaction mixture into an aqueous borate buffer solution at pH 8.5 to 9.0, which was held in the appropriate pH-range by addition of an aqueous ammonia solution. This procedure delivered crude yields of 72% to 81%, however also under these conditions purities were only between 75% and 85% and still 3.5% to 11% unreacted 14-hydroxycodeinone was present in the end-product.
Hence there is a need for a more efficient process with a higher yield whereby little or no unreacted starting material is found after work-up procedures. Additionally the use of the highly corrosive BBr3, which releases HBr fumes very easily upon contact with water, should be avoided.
The use of AlCl3 as a demethylation agent is described by Asnawi A. et al. in ITB J. Sci., vol. 43a, no. 1, 43-50 (2011) and by Burwell R. L. in Chem. Rev., 615-685 (1954).
It has now been found that O-demethylation of methoxy substituted morphinan-6-one derivatives of formula (II), e.g. 14-hydroxycodeinone, can be performed with a higher yield, higher purity, and little or no undesired hydration of the double bond, using AlCl3 as the demethylating agent in a reaction-inert solvent having a water content ranging from 0.1% wt to 0.8% wt.